Probiotics treatment improves cognitive impairment in patients and animals: A systematic review and meta-analysis

doi:10.1016/j.neubiorev.2020.10.027

Neuroscience & Biobehavioral Reviews

Volume 120, January 2021, Pages 159-172

https://doi.org/10.1016/j.neubiorev.2020.10.027 Get rights and content

Highlights

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A meta-analysis of probiotic intervention for cognitive function in humans and animals.
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The effects on cognitively impaired individuals were greater than healthy individuals.
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The therapeutic effect of one strain of probiotic supplement was greater than multiple probiotics in humans.
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Probiotics were effective therapy for improving cognition in cognitively impaired patients.
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We provide some suggestions for probiotics intervention and tend to support a customized approach for different individuals.

Abstract

The gut–brain axis has received considerable attention in recent years, and the “psychobiotics” concept indicates that probiotics have a potential positive effect on cognitive function. Therefore, the aim of this study was to quantitatively evaluate the influence of probiotics on cognition. We conducted a random-eﬀ ;ects meta-analysis of 7 controlled clinical trials and 11 animals studies to evaluate the eﬀ ;ects of probiotics on cognitive function. Probiotics supplementation enhanced cognitive function in both human (0.24 [0.05–0.42]; I² = 0 %) and animal studies (0.90 [0.47–1.34]; I² = 74 %). Subgroup analyses indicated that the effects of probiotics on cognitively impaired individuals (0.25 [0.05–0.45]; I² = 0 %) were greater than those on healthy ones (0.15 [−0.30 to 0.60]; I² = 0 %). Furthermore, compared with a multiple-probiotic supplement, a single strain of probiotics was more effective in humans. The meta-analysis provided some suggestions for probiotics intervention and tended to support a customized approach for different individuals to ameliorate cognitive disorders. Future additional clinical trials are necessary to evaluate therapeutic effect and influencing factors.

Introduction

“Cognitive decline” as a common symptom refers to deterioration in cognitive ability to varying degrees (Langa and Levine, 2014). Cognitive decline is a growing public-health concern and very common in a variety of conditions, including aging, adiposity, depression, and especially in Alzheimer disease (AD) (Small, 2016). The World Health Organization (WHO) reports that about 50 million people now suffer dementia, and that with one new case every 3 s the number of dementia patients is set to triple by 2050 (WHO, 2019). The continuous increase will not only lead to a decline in quality of life but also contribute to profound social and financial consequences (Wortmann, 2012). However, pharmacological treatment is limited, and no drugs to completely reverse the symptoms are available; related treatments are not effective in all of the patients and can even generate undesirable side effects (Galimberti et al., 2010). Therefore, finding a therapy to promote cognitive function is urgent.

The gut microbiome has emerged in recent decades as a critical factor affecting neurophysiological and psychophysiological functions, including cognition, emotion neurotransmission, and neurodevelopment (Sarkar et al., 2018). The interaction between gut microbes and the central nervous system (CNS) exists within the so-called “gut–brain axis” (Rosshart et al., 2017), a complex bidirectional-association network between intrinsic gut microbes and the brain (Palm et al., 2015). In recent years, several lines of studies have suggested that changes in the composition of the intestinal microbiota (including in germ-free [GF] mice), such as those created by bacterial infections, antibiotics or supplements of probiotics, significantly influence cognitive function positively or negatively (Collins et al., 2012; Gareau, 2014; Gareau et al., 2011; Messaoudi et al., 2011). Probiotics are defined as living microörganisms with potential health benefits to the host when administered (de J R De-Paula et al., 2018); as one means of changing the composition and function of gut microbiota, probiotics have proven capable of affecting cognitive function (Sarkar et al., 2018). Therefore, our supposition was that probiotics supplementation might be an effective therapy for improving cognitive function through optimizing the composition and function of gut microbiota.

However, although some researchers report that probiotics supplements can improve cognition, relevant data are still scarce, and various studies have had inconsistent results (Bhattacharjee and Lukiw, 2013; Davari et al., 2013). Furthermore, whether probiotics promote cognition lacks conclusive results in both humans and animals, and multiple sources of discrepancies also exist. Up to now, no relevant meta-analysis has yielded a positive and consistent conclusion. Therefore, the objective of our meta-analysis was to provide quantitative results of probiotics’ effects on cognitive function in humans and animals, as well as provide some suggestions on how to use potentially suitable probiotics.

Section snippets

Literature search strategy

We conducted a systematic literature search to identify studies on the influence of probiotics supplements on cognitive function in humans and animals. We searched three electronic databases (Cochrane Library, PubMed, and EMBASE) to find potentially pertinent articles up through December 2019 using Medical Subject Headings (MeSH) and free-text terms for “probiotic” OR “lactobacillus” OR “bifidobacterium” OR “Lactococcus” OR “Streptococcus” AND “memory” OR “cognitive” OR “executive function” OR

Study characteristics

The process of study selection is illustrated in Fig. 1. Our initial search strategy identified 3451 records: 578 from PubMed, 170 from Cochrane, 2699 from EMBASE, and 4 from other sources. Duplicate records were removed and irrelevant studies eliminated by keyword (review, case, report, letter, and meta-analysis), after which we screened titles and abstracts. This left 205 articles to be assessed by reading the full text. We removed 187 of these articles because they had inappropriate

Discussion

All of the human studies included were RCTs, which further enhanced the rigor and credibility of the studies. Based on our results, we found a positive overall effect of probiotics supplements on cognitive function. This effect was reflected in both humans (0.24 [0.05–0.42]; I² = 0 %; P = 0.01) and animals (0.90 [0.47–1.34]; I² = 74 %; P < 0.001). Furthermore, the included articles involved a variety of cognitive-disorder models, but the results still demonstrated positive effects on cognition.

Conclusion

Our meta-analysis showed that probiotics supplementation had an overall significant effect in promoting cognitive function in both humans and animals, and that probiotics could be effective and accessible cognitive therapy. Subgroup analyses found that probiotics supplements improved cognitive function in cognitively impaired individuals while having no significant effect on healthy people and possibly even being detrimental to them. Due to strain specificity and discrepancies in

Acknowledgments

This work was funded by Public Welfare Technology Applied Research Projects in Zhejiang Province (No. 2016C33191), Zhejiang Medical Health Science and Technology Project (No. 2019KY724, 2020KY332), the Scientific Research Fund of Shaoxing University (No. 20125025), and the National Training Program of Innovation and Entrepreneurship for College Students (No. 2017R10349001). We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

References (60)

E. Avolio et al.
Probiotics modify body weight together with anxiety states via pro-inflammatory factors in HFD-treated Syrian golden hamster
Behav. Brain Res.
(2019)
A.L. Carlson et al.
Infant gut microbiome associated with cognitive development
Biol. Psychiatry
(2018)
S. Davari et al.
Probiotics treatment improves diabetes-induced impairment of synaptic activity and cognitive function: behavioral and electrophysiological proofs for microbiome-gut-brain axis
Neuroscience
(2013)
V. de J R De-Paula et al.
Relevance of gutmicrobiota in cognition, behaviour and Alzheimer’s disease
Pharmacol. Res.
(2018)
L. Desbonnet et al.
The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat
J. Psychiatr. Res.
(2008)
S.M. Finegold et al.
Pyrosequencing study of fecal microflora of autistic and control children
Anaerobe
(2010)
J. Fujimoto et al.
Identification and quantification of Lactobacillus casei strain Shirota in human feces with strain-specific primers derived from randomly amplified polymorphic DNA
Int. J. Food Microbiol.
(2008)
H. Jiang et al.
Altered fecal microbiota composition in patients with major depressive disorder
Brain Behav. Immun.
(2015)
S. Liang et al.
Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress
Neuroscience
(2015)
R.T. Liu et al.
Prebiotics and probiotics for depression and anxiety: a systematic review and meta-analysis of controlled clinical trials
Neurosci. Biobehav. Rev.
(2019)

N.W. Palm et al.

Immune-microbiota interactions in health and disease

Clin. Immunol.

(2015)

R. Rodrigo et al.

Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy

Gastroenterology

(2010)

L. Rudzki et al.

Probiotic Lactobacillus Plantarum 299v decreases kynurenine concentration and improves cognitive functions in patients with major depression: a double-blind, randomized, placebo controlled study

Psychoneuroendocrinology

(2019)

S.M. Ryan et al.

Neuroinflammation negatively affects adult hippocampal neurogenesis and cognition: can exercise compensate?

Neurosci. Biobehav. Rev.

(2016)

A. Sarkar et al.

The microbiome in psychology and cognitive neuroscience

Trends Cogn. Sci.

(2018)

G.W. Small

Detection and prevention of cognitive decline

Am. J. Geriatr. Psychiatry

(2016)

S. Tillmann et al.

Probiotics reduce risk-taking behavior in the Elevated Plus Maze in the Flinders Sensitive Line rat model of depression

Behav. Brain Res.

(2019)

J.D. Wood

Enteric neuroimmunophysiology and pathophysiology

Gastroenterology

(2004)

A. Agahi et al.

Does severity of Alzheimer’s disease contribute to its responsiveness to modifying gut microbiota? A double blind clinical trial

Front. Neurol.

(2018)

A. Ait-Belgnaoui et al.

Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice

Neurogastroenterol. Motil.

(2014)

E. Akbari et al.

Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer’s disease: a randomized, double-blind and controlled trial

Front. Aging Neurosci.

(2016)

J.S. Bajaj et al.

Randomised clinical trial: lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis

Aliment. Pharmacol. Ther.

(2014)

J.E. Beilharz et al.

Cafeteria diet and probiotic therapy: cross talk among memory, neuroplasticity, serotonin receptors and gut microbiota in the rat

Mol. Psychiatry

(2018)

D. Benton et al.

Impact of consuming a milk drink containing a probiotic on mood and cognition

Eur. J. Clin. Nutr.

(2007)

S. Bhattacharjee et al.

Alzheimer’s disease and the microbiome

Front. Cell. Neurosci.

(2013)

M. Borenstein et al.

A basic introduction to fixed-effect and random-effects models for meta-analysis

Res. Synth. Methods

(2010)

G.J. Brewer

Why vitamin E therapy fails for treatment of Alzheimer’s disease

J. Alzheimers Dis.

(2010)

M. Carabotti et al.

The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems

Ann. Gastroenterol.

(2015)

R.J. Castellani et al.

Alzheimer disease pathology as a host response

J. Neuropathol. Exp. Neurol.

(2008)

T. Chunchai et al.

Decreased microglial activation through gut-brain axis by prebiotics, probiotics, or synbiotics effectively restored cognitive function in obese-insulin resistant rats

J. Neuroinflammation

(2018)

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¹: These authors contributed equally to this work.

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Review articleProbiotics treatment improves cognitive impairment in patients and animals: A systematic review and meta-analysis

Highlights

Abstract

Introduction

Section snippets

Literature search strategy

Study characteristics

Discussion

Conclusion

Acknowledgments

Behav. Brain Res.

Biol. Psychiatry

Neuroscience

Pharmacol. Res.

J. Psychiatr. Res.

Anaerobe

Int. J. Food Microbiol.

Brain Behav. Immun.

Neuroscience

Neurosci. Biobehav. Rev.

Clin. Immunol.

Gastroenterology

Psychoneuroendocrinology

Neurosci. Biobehav. Rev.

Trends Cogn. Sci.

Am. J. Geriatr. Psychiatry

Behav. Brain Res.

Gastroenterology

Does severity of Alzheimer’s disease contribute to its responsiveness to modifying gut microbiota? A double blind clinical trial

Front. Neurol.

Probiotic gut effect prevents the chronic psychological stress-induced brain activity abnormality in mice

Neurogastroenterol. Motil.

Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer’s disease: a randomized, double-blind and controlled trial

Front. Aging Neurosci.

Randomised clinical trial: lactobacillus GG modulates gut microbiome, metabolome and endotoxemia in patients with cirrhosis

Aliment. Pharmacol. Ther.

Cafeteria diet and probiotic therapy: cross talk among memory, neuroplasticity, serotonin receptors and gut microbiota in the rat

Mol. Psychiatry

Impact of consuming a milk drink containing a probiotic on mood and cognition

Eur. J. Clin. Nutr.

Alzheimer’s disease and the microbiome

Front. Cell. Neurosci.

A basic introduction to fixed-effect and random-effects models for meta-analysis

Res. Synth. Methods

Why vitamin E therapy fails for treatment of Alzheimer’s disease

J. Alzheimers Dis.

The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems

Ann. Gastroenterol.

Alzheimer disease pathology as a host response

J. Neuropathol. Exp. Neurol.

Decreased microglial activation through gut-brain axis by prebiotics, probiotics, or synbiotics effectively restored cognitive function in obese-insulin resistant rats

J. Neuroinflammation

Review article
Probiotics treatment improves cognitive impairment in patients and animals: A systematic review and meta-analysis